“I’m by no means an exception. Addison’s disease is often missed or diagnosed late. That early diagnosis can be a challenge is frequently addressed in the medical literature and many poignant examples can be read on patient forums. In fact I know very few prompt and swift diagnoses.”

“…But there are far more upsetting stories of other Addison crises. Even in this era there are unnecessary deaths due to inadequate intervention.”

While preparing this post I came across a recent paper in “Het Nederlands Tijdschrift voor Geneeskunde” (something like the Dutch Lancet) with a relevant clinical lesson on this very subject. It is entitled:

“Addisonian crisis in patients with known adrenal insufficiency: the importance of early intervention”, written by Mulder of the group of Professor Hermus from the Universitair Medisch Centrum St Radboud, Nijmegen.

The paper decribes 3 fatal cases of Addisonian crisis in patients with adrenal insufficiency, which formed the basis for the development of a regional protocolto prevent any further unnecessary death from Addisonian crisis (see PubMed abstract here).

Patient A was a 47 year old male with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Since this leads to deficient glucocorticoid and mineralocorticoid hormone production, replacement therapy consisted of daily replacement with glucocorticoid (hydrocortisone, HC) and mineralocorticoid (fludrocortisone).
A got a sudden gastroenteritis (acute abdominal pain, watery diarrhea, no fever), for which he doubled his HC dose. The next day he became weak and dizzy. The consulted physician didn’t deem parenteral cortisol (proposed by the patient’s partner) necessary, but prescribed loperamide instead. Indeed the diarrhea improved, but the condition of the patient worsened overnight, his temperature dropped to 34,4 C, he was confused and finally became comatose. Upon arrival at ED the hypotensive patient developed ventricular fibrillation. The neurological sequelae after CPR were so severe that active medical treatment was withheld, after which the patient died.

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The other two patients had panhypopituitarism and adrenal insufficiency secondary to theirACTH deficiency. With respect to replacement of adrenal hormones, these patients only require replacement of (ACTH driven production of) glucocorticoids, not mineralocorticoids. (On the other hand, they need extra replacement of other hypophysis-(regulated) hormones, like levothyroxine, gonadotropins and growth hormone).

Patient B, a 28 year old male got a sore throat and fever (41 C), for which he didn’t increase his HC-dose. His mother called a physician in vain: patient B didn’t respond and was found dead two hours later. Obduction showed tonsillitis, bronchopneumonia and an enlarged spleen, indicative of sepsis. This all took place in one and a half day.

Patient C was vomiting and had fever during a couple of days. Soon after her doctor visited her, she suffered a cardiac arrest and died. Her family physician was not familiar with her medical history nor with the prescribed medication. In retrospect, patient C had poor treatment compliance (never came to a consult and didn’t take replacement medication, including HC, for a year).

Conclusions

Even patients known to have adrenal insufficiency can develop a life-threatening Addison crisis in case of inadequate adjustment of the glucocorticoid dosage during intercurrent illness. Treatment consists of a high parenteral dose glucocorticoids, preferentially HC (because this also has a mineralocorticoid action).

The chance of hypovolemic shock accompanying a crisis is greater in patients with primary Addison, lacking mineralocorticoids (case A).

Preventive measures

These casualties led to a new protocol. According to the authors:

“Patients with known adrenal insufficiency, as well as their relatives and general practitioners, should repeatedly receive verbal and written instructions on how to deal with physical and severe psychic stress. We teach the patients and their relatives how to use an emergency injection of hydrocortisone, and the patients can consult the on-call endocrinologist by telephone 24 hours a day.”

I. Points to be adressed in the yearly instruction of patients with primary or secondary adrenal insufficiency, preferably in presence of his/her partner or close relative:

explain importance of glucocorticoid use.

describe the symptoms of an Addisonian crisis

give instruction on increasing glucocorticoid dose in case of illness or severe stress

stress the importance of an alert bracelet

verify whether the patient has an emergency ampule with hydrocortisone (i.e. Solucortef) at home

give instruction on the use of an emergency intramuscular injection (standardly given by a nurse)

inquire about traveling abroad, provide letter with advice in case of (written in English) if required*

provide written information, including telephone number of on-call endocrinologist (24 hours a day service)!!

In addition the family physician receives a yearly letter with a standard treatment advice in case of an imminent Addisonian crisis. He is advised to inform his colleagues at the Central GP post.

II. Advice to patients with primary or secondary adrenal insufficiency for dosage of cortisone in case of stress. Normal Dose is 15 to 30 mg HC daily (or equivalent dose of other glucocorticoid)

fever (>38 C), severe psychological stress** (difficult exam, death family member): at least triple HC-dose, i.e. 60 mg in the morning and 30 mg in the evening, taper till normal dose after symptoms are relieved. Contact doctor if there is no improvement.

surgery or hospitalization:the treating physician should contact the patient’s endocrinologist for advice on dose adjustments.

What is special about this protocol is the 24h endocrinologist on call service, the earlier (and consistent) referral to endocrinologists and ED, in case of possible emergency, and the structural approach: all patients with adrenal insufficiency, including their relatives and physicians, are well-informed about the preventive measures that should be taken (including HC emergency ampule and alert bracelet).

That is a great improvement! Hopefully other regions and countries will follow this example.

* The Dutch Addison and Cushing Society NVACP since long has a small booklet “SOS stressboekje”, which is specially designed to inform physicians abroad when on vacation. Short guidelines for dosages of (hydro)cortisone in stress and medical information for physicians is translated in 6 languages.

** Advices based on what is usually advised in the literature. There is little evidence for a particular dose in case of physical or psychological stress.